Long-term potentiation of synaptic transmission in the hippocampus (LTP) is a well-characterized, tractable model system for the study of mammalian learning and memory. Not only does a wide variety of evidence support a role for LTP in memory acquisition, the discrete, compact structure of the hippocampus allows for convenient monitoring of electrophysiological responses, and relative ease of in vitro manipulation. The development of the hippocampal slice preparation as a means to study LTP has provided a system in which to study the molecular and biophysical basis for this effect. The studies described in this application focus on the molecular mechanisms underlying the maintenance of LTP in the CA1 region of rat hippocampus. Using a variety of biochemical and pharmacological methods and approaches, we will investigate the involvement of protein kinase C in the maintenance of LTP. Specifically, the studies will address the following questions: By what mechanism is protein kinase C persistently activated in the maintenance phase of NMDA receptor-dependent LTP? How is the persistent activation of PKC reversed by depotentiating stimulation? These studies will serve as the foundation for future studies exploring in greater detail the biochemical mechanisms contributing to this form of synaptic plasticity, and should provide insight into mechanisms involved in long- lasting changes in neuronal function in the mammalian CNS. This in turn should increase our understanding of mechanisms for the development and prolongation of a variety of neuropsychiatric disorders.